Received: 7 August 2022 Revised: 28 January 2023 Accepted: 3 February 2023

DOI: 10.1002/glia.24353

REVIEW ARTICLE

The role of glial cells in Zika virus-induced neurodegeneration

André Quincozes-Santos 1,2,3 | Larissa Daniele Bobermin 2 |

Naithan Ludian Fernandes Costa 2 | Natalie K. Thomaz 3 |
Rômulo Rodrigo de Souza Almeida 3 | Walter O. Beys-da-Silva 4 | Lucélia Santi 4 |
Rafael L. Rosa 4 | Daniela Capra 5 | Juliana M. Coelho-Aguiar 6 |
Marcos Fabio DosSantos 7 | Manoela Heringer 5 | Elizabeth O. Cirne-Lima 4 |
Jorge Almeida Guimarães 4 | Lavínia Schuler-Faccini 4 |
Carlos-Alberto Gonçalves 1,2,3 | Vivaldo Moura-Neto 5,6 | Diogo Onofre Souza 1,3
1
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
2

s-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
Programa de Po
3

s-Graduação em Ciências Biolo
Programa de Po
gicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre,
RS, Brazil
4
Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
5
Instituto Estadual do Cérebro Paulo Niemeyer, Secretaria Estadual de Saúde do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
6

rio de Morfogênese Celular, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
Laborato
7

rio de Propriedades Mecânicas e Biologia Celular, Faculdade de Odontologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
Laborato

Correspondence
André Quincozes-Santos, Laborato
rio de Abstract
Neurotoxicidade e Glioproteção (LABGLIO),
Zika virus (ZIKV) is a strongly neurotropic flavivirus whose infection has been associ-
Departamento de Bioquímica, Universidade
Federal do Rio Grande do Sul, Rua Ramiro ated with microcephaly in neonates. However, clinical and experimental evidence
Barcelos, 2600 – Anexo, Bairro Santa Cecília.
indicate that ZIKV also affects the adult nervous system. In this regard, in vitro and
90035–003 Porto Alegre, RS, Brazil.
Email: andrequincozes@ufrgs.br in vivo studies have shown the ability of ZIKV to infect glial cells. In the central ner-
vous system (CNS), glial cells are represented by astrocytes, microglia, and oligoden-
Funding information
Conselho Nacional de Desenvolvimento drocytes. In contrast, the peripheral nervous system (PNS) constitutes a highly

gico; Coordenação de
Científico e Tecnolo
heterogeneous group of cells (Schwann cells, satellite glial cells, and enteric glial cells)
Aperfeiçoamento Pessoal de Nível Superior
(CAPES); Fundação de Amparo à Pesquisa do spread through the body. These cells are critical in both physiological and pathological
Estado do Rio Grande do Sul (FAPERGS);
conditions; as such, ZIKV-induced glial dysfunctions can be associated with the devel-
Ministry of Science, Technology, Innovation
and Communications (MCTIC), Ministry of opment and progression of neurological complications, including those related to the
Education (MEC), Ministry of Health (MS),
adult and aging brain. This review will address the effects of ZIKV infection on CNS
Grant/Award Numbers: Edital MCTIC/
FNDCT-CNPq/MEC-CAPES/MS-Decit/No and PNS glial cells, focusing on cellular and molecular mechanisms, including changes
14/2016, project 440763/2016-9
in the inflammatory response, oxidative stress, mitochondrial dysfunction, Ca2+ and
glutamate homeostasis, neural metabolism, and neuron–glia communication. Of note,
preventive and therapeutic strategies that focus on glial cells may emerge to delay
and/or prevent the development of ZIKV-induced neurodegeneration and its
consequences.

André Quincozes-Santos and Larissa Daniele Bobermin contributed equally to this work.

Glia. 2023;71:1791–1803. wileyonlinelibrary.com/journal/glia © 2023 Wiley Periodicals LLC. 1791

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1792 QUINCOZES-SANTOS ET AL.

KEYWORDS
glial cells, inflammatory response, neurodegeneration, neuron–glia communication, Zika virus

1 | I N T RO DU CT I O N were documented in children, and the virus was identified as a human

In 2016, the World Health Organization declared Zika virus (ZIKV)
infection as a ‘Public Health Emergency of International Interest”, not
only because of the high risk of disease transmission, but also due to
the neurological consequences that began to be observed on a large
scale, in children and adults. ZIKV is an arbovirus that was first identi-
fied and isolated in 1947 in Rhesus monkeys from the Zika forest of
Uganda. This virus belongs to the family Flaviviridae and is mainly
transmitted by Aedes mosquitoes. ZIKV was endemic, with few cases
reported in humans in Africa and Asia until 2007, when its geographic
distribution spread, reaching the Yap Islands (in 2007), French Polyne-
sia (in 2013), and the Americas (in 2015) (Musso et al., 2019).
ZIKV can infect several body sites, including the eyes, cardiac
tissue, the gastrointestinal (GI) system, reproductive tract, placenta,
and central nervous system (CNS) (Figure 1) (Gasco & Muñoz-
Fernández, 2020; Rossi et al., 2020; Ryan et al., 2021; Zafar
et al., 2021). The most common symptoms of acute ZIKV infection
include fever, headaches, myalgias, rash, and conjunctivitis. Less fre-
quent symptoms have also been reported, such as diarrhea, edema,
and retro-orbital eye pain (Petersen et al., 2016; Rawal et al., 2016).
After the ZIKV outbreak in Brazil at 2015, neurological symptoms
teratogen and associated with clinical manifestations, including micro-
cephaly, which were collectively named congenital Zika syndrome
(CZS) (Schuler-Faccini et al., 2022). According to a database of imaging
studies, cranial characteristics of children with microcephaly were
described, including a substantial increase in ventricle volumes, corti-
cal and subcortical atrophy, cerebellar hypoplasia and abnormalities in
the white matter, corpus callosum, basal ganglia, and trunk, as well as
calcifications in different brain regions (Schuler-Faccini et al., 2022;
Wu et al., 2018). Moreover, diagnosis of autism spectrum disorders
(ASD) in childhood were recently correlated with ZIKV infection dur-
ing pregnancy (Santi et al., 2021; Vianna et al., 2018).
In addition, current clinical data show that ZIKV infection affects
the adult brain, causing neurological complications, including Guillain-
Barré, seizures, and other myelitis and encephalitis-like illnesses
(Carteaux et al., 2016; Ferrari-Marinho et al., 2022; Henriques-Souza
et al., 2017). Neuroimaging findings indicate changes in the adult
human brain structure and functional organization, comprising both
motor-related and nonsomatomotor regions (Bido-Medina
et al., 2018; Ferrari-Marinho et al., 2022). Furthermore, accumulating
experimental evidence has demonstrated the ability of ZIKV to infect
neural cells and replicate in adult brain tissue, being able to affect

F I G U R E 1 Schematic illustration of Zika virus (ZIKV) infection in body organs, pregnant women, and children. ZIKV can infect several cell
types, including eye, cardiac, gastrointestinal, reproductive tract, placenta, and central nervous system cells (a). In pregnant women, viral
transmission can occur through the placenta (b). Due to ZIKV neurotropism, infections can impair brain development in infants/children, even in
the absence of evident structural brain abnormalities and microcephaly (c).

QUINCOZES-SANTOS ET AL.
synapses and induce cognitive deficits (Figueiredo et al., 2019). The
areas of most significant infection were reported to be the regions of
cognitive processing and memory (frontal cortex and hippocampus)
and motor area (striatum) (Figueiredo et al., 2019). ZIKV has also been
detected in cerebrospinal fluid (CSF) and the brain tissue of children
with CZS, and in adult patients with neurological complications
(Alves-Leon et al., 2019; Figueiredo et al., 2019; Mlakar et al., 2016;
Schuler-Faccini et al., 2022), reinforcing its neurotropism.
It is important to note that although ZIKV infection can be tran-
sient, it can induce significant changes in adult brain functionality with
potential impact on the pathogenesis of neurodegenerative diseases,
which mostly involve glial cells. Thus, in this review, we will discuss
the role of glial cells as central players in the neurodegenerative com-
plications associated with ZIKV infection.
2 | G LI A L C EL L S : OR I G I N S A N D
FUNCTIONS
The term “glial cells”, or the concept of “neuroglia,” is based on the
collective function that these types of cells play in nervous system
homeostasis, regardless of their distinct structure, specific functions,
and embryonic origins (Verkhratsky et al., 2019). Glial cells were previ-
ously mischaracterized as a mere sort of “glue” for adjoining neurons
without further, more complex functions (García-Marín et al., 2007;
Jäkel & Dimou, 2017). From this concept arose the name glia (from
the ancient Greek word “glía” and the German word “Nervenkitt”,
both meaning “glia” in English). However, several functions have since
been attributed to glial cells, including synapse formation, regulation
of synaptic transmission and plasticity, redox balance, ion and water
homeostasis, maintenance of the blood–brain barrier (BBB), control of
the toxicity formed in the extracellular space, and the establishment
of myelin sheets (Jäkel & Dimou, 2017).
In addition, glial cells not only act in healthy states, but are also
crucial in pathological conditions, a topic that has been extensively
studied. In this regard, glial cells display immune and inflammatory
functions, which affect the progression and neurological conse-
quences of virus infections (Inglis et al., 2016; Li, Wang, et al., 2018;
Meertens et al., 2017). Glial cells are found in the CNS, where they
are represented by microglia, astrocytes, oligodendrocytes and oligo-
dendrocyte progenitor cells (OPCs), and in the peripheral nervous sys-
tem (PNS), where they are composed of a highly heterogeneous
group of cells spread through the body. Peripheral glial cells include
Schwann cells, satellite glial cells, and enteric glial cells, among others
(Mai & Paxinos, 2012).
3 | GLIAL CELLS AS TARGETS OF ZIKV
INFECTION
ZIKV infection strongly affects the cytoarchitecture of the brain and
specific neurochemical and molecular functions of the neural cells,
including glial fibrillary acidic protein (GFAP) positive cells (Devhare
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1793
et al., 2017; Liang et al., 2016). In vitro and in vivo experimental
models indicate that pathological mechanisms of CZS, as well as the
progression and clinical outcomes of ZIKV infection, are closely asso-
ciated with neuron–glia communication (Beys-da-Silva et al., 2020;
Bobermin et al., 2020; Greenhalgh et al., 2020; Ledur et al., 2020). In
addition, glial cells have a wide range of adaptive functions that regu-
late tissue recovery after injury, since dysfunctions in these cells may
represent a risk factor for neurodegenerative and neuropsychiatric
diseases, and consequently, for ZIKV-induced neurodegeneration
(Labzin et al., 2018; Li et al., 2021; Mehta et al., 2013).
Additionally, there is a close relationship between ZIKV and glial
cells whereby; (i) astrocytes present the AXL receptor, a candidate
receptor in neural cells for promoting ZIKV infection (Chen
et al., 2018; Meertens et al., 2017), and roles of astrocytes in produc-
tive infection and possibly as a ZIKV reservoir have been demon-
strated (Huang et al., 2018; Stefanik et al., 2018); (ii) oligodendrocytes
are the myelin-producing cells that insulate axons to allow saltatory
conduction; previous findings have reported their susceptibility to
ZIKV infection (Musso et al., 2019; Schultz, Cumberworth,
et al., 2021), and ZIKV-induced impairment in OPC differentiation and
oligodendrocyte development (Li, Wang, et al., 2018); (iii) microglia
are the CNS resident immune cells, are proposed to be targets of
ZIKV, and mediate neuroinflammation after ZIKV exposure (Meertens
et al., 2017; Rombi et al., 2020); and (iv) Guillain-Barré syndrome,
which is related to peripheral glial cells, has been described during
ZIKV outbreaks (Musso et al., 2019; Rombi et al., 2020). Figure 2 sum-
marizes the main effects of ZIKV in glial cells, which are addressed in
the following sections.
3.1 | Effects of ZIKV on glial metabolism, oxidative
stress, and glutamate homeostasis
Astrocytes contain numerous stellate processes, due to their specific
morphology and intimate contact with synapses, blood vessels, and
other glial cells. ZIKV infection triggers morphological changes in
astrocytes (Huang et al., 2018; Stefanik et al., 2018). In addition,
astrocytes support neurons through metabolic coupling between syn-
aptic activity and glucose utilization (neurometabolic coupling)
(Bélanger et al., 2011), a classic example of neuron–glia interaction.
The metabolic activity of neural cells can be reprogrammed in
response to redox and inflammatory challenges (Lynch, 2020); more-
over, increased glucose consumption may be needed for viral replica-
tion, leading to energy stress in brain cells. It has been hypothesized
that ZIKV replication may increase glucose uptake through the
GLUT-1 glucose transporter, similar to Dengue virus (Fontaine
et al., 2015; Gilbert-Jaramillo et al., 2019). While increased glycolysis
produces ATP rapidly for viral replication, it also contributes to endo-
plasmic reticulum stress, mitochondrial dysfunction, elevated reactive
oxygen species (ROS) production and dysregulated autophagy, which
lead to cell death (Gilbert-Jaramillo et al., 2019). In immune cells, gly-
colytic enzymes also trigger hypoxia inducible factor 1α (HIF1α), the
production of interleukin-1β (IL-1β) and inflammasome activation

1794
F I G U R E 2 Zika virus (ZIKV)-induced glial dysfunctions potentially
associated with neurodegeneration. ZIKV infection can induce several
functional changes in glial cells, including inflammatory responses,
oxidative stress, and mitochondrial dysfunction, as well as alterations
in Ca2+ and glutamate homeostasis, metabolism, and neuron–glia
communication. These changes may converge to cause
neurodegeneration. Functional glial cells are represented by ramified
astrocyte (blue) and microglia (yellow), and oligodendrocyte in purple.
Dysfunctional glial cells are represented by astrocyte (blue) and
microglia (yellow) with enlarged cell bodies, and oligodendrocytes in
gray. Functional (left) and damaged (right) neurons are represented in
the center, and ZIKV is represented by yellow circles.
(Hughes & O'Neill, 2018; Palsson-McDermott et al., 2015), while inhi-
bition of the glycolytic pathway can revert neuroinflammation
(Vizuete et al., 2022).
It is also important to emphasize that an experimental in vitro
model of ZIKV infection was found to present significant mitochon-
drial failure, oxidative stress, and DNA damage in human iPSC-derived
astrocytes (Ledur et al., 2020). In the glial cell line, U87-MG, ZIKV
infection induced an increase in the production of ROS, lipid peroxida-
tion, and protein carbonylation, in addition to decreased activities of
the catalase (CAT) and the superoxide dismutase (SOD) enzymes, in
association with a decrease in nuclear factor erythroid 2-related factor
2 (Nrf2) activation (Almeida et al., 2020). Furthermore, oxidative
stress, associated with antioxidant depletion, was found in the brain
of ZIKV-infected mice (Almeida et al., 2020). Thus, astrocytes are criti-
cal for controlling redox homeostasis, and changes in this function can
impair the adult brain, contributing to further neurological manifesta-
tions related to ZIKV infection (Jiwaji & Hardingham, 2022; Ledur
et al., 2020; Schreiner et al., 2015).
Dysfunctions in mitochondrial activity may lead to incorrect func-
tioning of specific astrocyte proteins, such as glutamate transporters
(Allaman et al., 2011). Glutamate is the major excitatory
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QUINCOZES-SANTOS ET AL.
neurotransmitter in the mammalian CNS. However, an excessive con-
centration of glutamate in the synaptic cleft is implicated in the patho-
genesis of several brain disorders, a phenomenon termed
excitotoxicity (Allaman et al., 2011). Astrocytes are responsible for the
glutamate uptake and the regulation of extracellular levels of gluta-
mate. The impairment of glutamate transporters causes excitotoxicity,
which is potentiated by Ca2+ release from the mitochondria and
endoplasmic reticulum. In iPSC-derived astrocytes, ZIKV interfered
with Ca2+ uptake by mitochondria, increasing oxidative stress and cell
damage (Ledur et al., 2020). It is noteworthy that brain disorders share
common pathomechanisms (Lewerenz & Maher, 2015; Mehta
et al., 2013), therefore, changes in glial metabolism, redox and gluta-
mate homeostasis induced by ZIKV can impair the adult brain and
contribute to further neurological manifestations related to ZIKV
infection.
3.2 | Induction of glial cell-mediated
neuroinflammation by ZIKV
Astrocytes and microglia have a critical role in brain pathophysiology
and influence immunological processes and events caused by ZIKV
infection (Rombi et al., 2020). These glial cells synthesize and release
several cytokines and chemokines (Vainchtein & Molofsky, 2020),
where the inflammatory process constitutes a primary event connect-
ing ZIKV infection and glial cells. ZIKV triggers innate antiviral immune
responses, such as activation of the NLR family pyrin domain contain-
ing 3 (NLRP3) inflammasome and subsequent release of IL-1β in glial
cells, inducing cell death (Tricarico et al., 2017). Moreover, ZIKV infec-
tion increases the expression of Toll-like receptors (TLR2 and TLR3),
which in turn can mediate viral-induced inflammatory response and
replication in astrocytes (Bobermin et al., 2020; Ojha et al., 2019).
Interestingly, prolonged infection of astrocytes may lead to the spread
of infection to other cell types, inducing inflammation and further
damage, even in uninfected cells, due to astrocyte loss (Retallack
et al., 2016). In contrast, astrocytes are suggested to have a role in
limiting the spread of ZIKV, since infection of primary human astro-
cytes induced the production of type I interferon, preventing the
virus-induced killing of the cells (Lindqvist et al., 2016). In addition,
astrocytes form functional barriers such as the BBB, which restrict the
entry of inflammatory mediators into the CNS (Greenhalgh
et al., 2020). However, this function can be compromised by ZIKV
infection since its pathophysiological and immunological features indi-
cate that the cytokine storm may affect BBB permeability
(Vainchtein & Molofsky, 2020). In line with this, the CSF contains a
variety of immune cells that are related to adaptive immunity, and
ZIKV has also been detected in the CSF (França et al., 2016). Thus,
astrocytes can contribute to propagating the development and pro-
gression of ZIKV infection in the CNS, causing the injury of neural
cells through direct infection-induced and/or indirect immune-
mediated mechanisms (Rombi et al., 2020).
Although microglial cells can adopt the inflammatory phenotype
to exert neuroprotective functions, the persistent activation of

QUINCOZES-SANTOS ET AL.
microglia can be associated with chronic neuroinflammation, a fact
related to neurodegenerative and neuropsychiatric disorders. In this
context, neuroinflammation is a mutual feature of congenital micro-
cephaly in newborns and neurological complications in childhood and
adults (Maucourant et al., 2019). Furthermore, ZIKV infection of
microglial cells can inhibit cell proliferation and neuronal differentia-
tion of neural precursor cells (Lum et al., 2017; Wang et al., 2018), as
well as microgliosis in the brain of adult mice, particularly in the hippo-
campus, suggesting a role for these cells in the control of ZIKV replica-
tion and/or its elimination in the brain (Enlow et al., 2021; Figueiredo
et al., 2019). Consistent with this hypothesis, experimental models of
flavivirus infection, including ZIKV, can cause brain lesions in the hip-
pocampus of mice, where infiltrated macrophages and resident micro-
glia are significantly increased. Moreover, T cell-derived interferon-γ
(IFN-γ) signaling is required for microglial activation and seems to be
involved in ZIKV post-infection cognitive sequelae by eliminating pre-
and post-synaptic terminals (Garber et al., 2019). Flaviviruses can also
promote type 1 macrophage polarization in the brain, which is associ-
ated with encephalitic severity (Jhan et al., 2021). Other experimental
data from the infected brain of mice indicate that ZIKV with high
pathogenicity may induce sustained activation of the immune system,
including macrophage activation, leading to nerve tissue damage
(Shang et al., 2022). ZIKV may also evade host innate immune
response in macrophages and glial cells, which could facilitate viral
replication and dissemination in these cells (Gim et al., 2019). There-
fore, in cooperation with resident microglia, macrophage activation
may facilitate CNS inflammation and neurotoxicity during ZIKV
infection.
ZIKV can also directly affect oligodendroglia, infecting glial pro-
genitors during development, and disturbing oligodendrocyte func-
tionality, accompanied by immune response and microglial activation
(Li, Wang, et al., 2018; Schultz, Barrie, et al., 2021; Zhang et al., 2017).
In mature myelinated CNS cultures, ZIKV infection damages myelin-
ated fibers (Cumberworth et al., 2017; Schultz, Barrie, et al., 2021). Of
note, oligodendrocyte cell death might lead to secondary autoimmune
demyelination (Molina-Gonzalez et al., 2022), and these observations
are critical for understanding the effects of ZIKV in the mature CNS.
3.3 | ZIKV affects neuron–glia communication
ZIKV can affect numerous signaling pathways that play critical roles in
the crosstalk between metabolism, inflammatory response, and oxida-
tive systems, affecting neuron–glia communication. In astrocytes,
ZIKV dysregulates gene expression and pathways associated with
essential functions/processes, including metabolism and lipid biosyn-
thesis, glial differentiation, neurogenesis, and brain development,
along with pathways such as phosphoinositide-3-kinase (PI3K)/Akt
(Schouest et al., 2021; Shereen et al., 2021). These data agree with a
previous study from our group that showed that ZIKV potentially
induces reprogramming of the cellular metabolic machinery
and inhibits autophagy, neurogenesis, and immune response
(Beys-da-Silva et al., 2019).
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1795
Peripheral infection of adult knockout mice for the type-I inter-
feron receptor gene (A129 mice), which have an inefficient interferon
response, are associated with high levels of viral RNA in all analyzed
regions of the brain (Figueiredo et al., 2019). Upregulation of tumor
necrosis factor α (TNF-α) and complement system proteins C1q and C3
can impact neuron–glia communication, and consequently, the onset of
neurodegeneration (Figueiredo et al., 2019). In hippocampal slices from
adult rats, acute exposure to ZIKV caused significant cellular alterations
regarding redox homeostasis, inflammatory processes, neurotrophic
functions, glial commitment, and molecular signaling pathways, which
potentially affect important aspects of neuron–glia communication.
Moreover, ZIKV-induced neuroinflammation can involve Nrf2 and
nuclear factor kappa B (NFκB) pathways (Bobermin et al., 2020). Nrf2 is
a transcription factor involved in the adaptive responses to oxidative
stress and inflammation through their target genes. As such, there is an
interplay between Nrf2 and NFκB signaling, which may be critical
mechanistic partners in the altered neuron–glial communication
observed after ZIKV exposure (Bobermin et al., 2020). Accordingly,
NFκB can control energy homeostasis and metabolic adaptation by reg-
ulating mitochondrial respiration, and reprogramming cellular bioener-
getic pathways toward glucose metabolism, which requires an
orchestrated regulation between neurons and glial cells in the CNS
(Mauro et al., 2011). In addition, NFκB triggers an inflammatory
response by increasing pro-inflammatory cytokines that may induce
persistent neuroinflammation (Lima et al., 2019). As such, it is vital to
consider the link between metabolic and inflammatory signatures and
their consequences on neuron–glia coupling (Lynch, 2020). NFκB can
also regulate glutamate transporter activity (Ghosh et al., 2011), which
might link mitochondrial-mediated ROS overproduction, inflammatory
response, and excitotoxicity. These events are the basis of a number of
neurological and functional disabilities, including Alzheimer's disease
(AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and
multiple sclerosis, among others (Bhat et al., 2015; Labzin et al., 2018;
Verma et al., 2022), which may be associated with different clinical out-
comes after a patient's recovery from acute ZIKV infection.
Astrocytes synthesize and release a wide range of signaling mole-
cules, including gliotransmitters, and can therefore affect other glial
cells and neurons through the gliotransmission process, which is
closely associated with the “gliocrine system” (Vardjan et al., 2019).
As such, the release of gliosignaling molecules (Vardjan et al., 2019)
can occur through vesicular exocytosis or by carrier-mediated trans-
port or channel flux through the plasma membrane, which seems to
be activated mainly under pathological conditions (Gundersen
et al., 2015; Vardjan & Zorec, 2015). Homeostatic imbalance and
astroglial vesicular displacement contribute to the pathophysiology of
neurodegenerative diseases, including AD, Huntington's disease, and
neuroinfections, such as ZIKV (Zorec et al., 2018).
Finally, the glial reactivity/glial activation observed in experimental
models and studies with post-mortem brains (Bobermin et al., 2020;
Enlow et al., 2021; Figueiredo et al., 2019; Ledur et al., 2020) may eluci-
date the effects of ZIKV infection on neuronal loss and neurological def-
icit, emphasizing the role of neuron–glia communication in explaining
the pathogenesis of CZS and other neurological diseases associated with
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1796 QUINCOZES-SANTOS ET AL.

ZIKV. Table 1 displays important publications investigating the effects
of ZIKV on CNS cells, particularly glial cells, in this review.
3.4 | The role of glial cells in ZIKV
infection-induced alterations in neurosensory
pathways, peripheral and enteric nervous system
Previous studies conducted in mice demonstrated that ZIKV infection
targets peripheral neural phenotypes derived from the neural crest
(NC). ZIKV can productively infect human NC cells and peripheral
neurons derived from human pluripotent stem cells (hPSCs), inducing
increased cell death and transcriptional dysregulation. The presence
of ZIKV in Schwann cells differentiated from hPSCs has also been
observed (Oh et al., 2017). Schwann cells are among the most impor-
tant peripheral glial cells. They form the myelin sheet, which sur-
rounds the axons of the peripheral nerves in a spiral manner
(Verkhratsky et al., 2019). ZIKV infection and replication has been
demonstrated in human Schwann cells, which may lead to myelin dis-
ruption and peripheral neuropathies, such as Guillain-Barré syndrome

TABLE 1 Effects of Zika virus on glial cells

Experimental models Main findings Reference

In vitro
CNS and PNS myelinating cultures ZIKV infection is enhanced in the absence of the type I interferon; CNS axons Cumberworth
and myelinating oligodendrocytes are especially vulnerable, compared to PNS et al., 2017
cells
hPSC-derived astrocytes, U87 cells AXL blocking reduced ZIKV infection; azithromycin reduced viral proliferation Retallack et al., 2016
and organotypic culture and cytopathic effects
Human astrocytes AXL promotes ZIKV infection by antagonizing type I IFN signaling Chen et al., 2018
Human astrocytes AXL is important to ZIKV infection; ZIKV activated autophagy and inflammatory Ojha et al., 2019
responses by TLR pathway
Human astrocytes ZIKV infection through AXL modulates the innate response Meertens et al., 2017
Human astrocytes ZIKV specifically infects GFAP and S100B-positive astrocytes Huang et al., 2018
Human astrocytes Expression of cytokines/chemokines Stefanik et al., 2018
Human microglia Inflammatory response Lum et al., 2017
iPSC-derived astrocytes Glial reactivity, ROS imbalance, mitochondrial defects and DNA breakage Ledur et al., 2020
Mice astrocytes Astrocytes mediate a local IFN response within the CNS during flavivirus Lindqvist et al., 2016
infection.
Mouse astrocytes and human Dysregulation in the expression of pathways associated with cell death, Shereen et al., 2021
astroglioma metabolism, transcription, DNA replication and repair, cell cycle, and viral
responses
Murine embryonic spinal cord Signs of myelin damage, alongside axonal injury and diminished axonal density; Schultz, Barrie,
cell-derived and CNS myelinating upregulation of factors that have been linked to reduced myelination and et al., 2021
cultures demyelination
Rat hippocampal slices Inflammatory response, redox imbalance, modulation of neurotrophic factor Bobermin et al., 2020
release and changes in the expression of neuron-glial signaling pathways
Rhesus macaque astrocytes Induction of pathways associated with cell death, viral replication, metabolic and Schouest et al., 2021
lipid biosynthesis
In vivo
C57BL/6 mice Oxidative stress and decrease in antioxidant enzyme activities in vitro and in vivo Almeida et al., 2020
C57BL/6 J, Ifngr1 / , Ifngr f/fl and Neuroinflammation, neuronal loss in the hippocampus and microglial activation Garber et al., 2019
CX3CR1-CreERT mice
C57BL/6 mice, Swiss mice, Brain inflammation with microglial activation, phagocytosis of hippocampal Figueiredo et al., 2019
Il1r / mice and adult human synapses and memory impairment in mice; ZIKV replicates in adult human
cortical slices brain tissue
Ifnar1 knockout Apoptosis in early myelinating oligodendrocytes in white matter Schultz, Cumberworth,
et al., 2021
Mouse Neuronal cell death, abolishment of oligodendrocyte development, and immune Zhang et al., 2017
response

Note: In vitro and in vivo experimental models focusing on the effects of Zika virus on neuron-glial cellular and molecular mechanisms associated with
neurodegenerative diseases.
Abbreviations: BBB, blood–brain barrier; CNS, central nervous system; GFAP, glial fibrillary acidic protein; IFN, interferon; PNS, peripheral nervous system;
ROS, reactive oxygen species; TLR, toll-like receptors; ZIKV, Zika virus.

QUINCOZES-SANTOS ET AL.
(Dhiman et al., 2019; Volpi et al., 2018). Schwann cells also escheat
the central processes of the spiral (cochlear) ganglion axons, a group
of neuron cells located within the cochlea's modiolus (Carricondo &

mez, 2019).
Romero-Go
ZIKV can also change the auditory pathway (de Barbosa
et al., 2019; Inglis et al., 2016) and induce sensorineural hearing loss
(Leal et al., 2016), possibly due to a direct action in the cochlea, as also
observed for other congenital viral infections. Therefore, it may be
hypothesized that ZIKV may efficiently replicate along the glial cells
present in the auditory system, leading to hearing loss and CNS
effects/dysfunctions. In addition, ZIKV can replicate in the olfactory
ensheathing cells, the glial cells associated with the olfactory system
(Mutso et al., 2020). These cells also surround and support the axons
of olfactory neurons throughout their trajectory from the olfactory
mucosa to the olfactory bulb (Ekberg & St john, 2014). In this scenario,
the olfactory pathway represents a route that can be used by different
types of bacteria and viruses to reach the brain (St. John et al., 2016).
Remarkably, the findings that both olfactory ensheathing glial cells
and brain microvascular cells support ZIKV replication may relate to
the ability of the virus to enter the CNS via the olfactory nerve or
through the BBB (Mutso et al., 2020). Moreover, it should be noted
that, in adults, sensory changes in auditory and olfactory pathways
may also precede symptoms of neurodegenerative diseases such as
AD and PD (Shad et al., 2022; Ubeda-Bañon et al., 2020).
Although considered unusual and rarely mentioned in the litera-
ture, GI symptoms are among the most related to ZIKV infection
(Bôtto-Menezes et al., 2019; Li, Deng, et al., 2018; Rawal et al., 2016).
The injection of ZIKV into A129 mice was found to infect the myen-
teric plexus of the small intestine (more specifically in the jejunum)
(Oh et al., 2017), but little is known regarding the effects of ZIKV
infection on the GI tract and the enteric nervous system. The enteric
glia show great plasticity, with a high proliferation capacity and are
able to act as progenitor cells and differentiate into neurons in specific
situations (Gershon, 2011; Veríssimo et al., 2019). In contrast to previ-
ous evidence that did not identify enteric glia ZIKV infection
(Martínez et al., 2020), our preliminary findings obtained in a cell line
of rat enteric glial cells show that the enteric glia may be persistently
and productively infected with ZIKV (data not shown). However, the
hypothesis that the enteric glia is affected by ZIKV infection in vivo,
as well as the possible consequences of this infection, have yet to be
demonstrated. Of note, accumulating evidence has revealed that GI
disorders are possible pathological initiators of PD many years before
it progresses to the CNS, with an important role for enteric glial cells
(Yang et al., 2022).
4 | ZIKV INFECTION AND POTENTIAL
N E U R O L O G I CA L C O M P L I C A T I O N S R E L A T E D
TO THE A DU LT AND A G I NG B R AIN
Pathological processes in adult and aging brains are commonly associ-
ated with the triad neuroinflammation, oxidative stress, and glutamate
excitotoxicity, which are intimately related to functions of glial cells
10981136, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/glia.24353 by UNSA - Univ Nacional de Salta, Wiley Online Library on [06/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1797
(Coulter & Eid, 2012; Labzin et al., 2018; Mattson &
Arumugam, 2018; Quincozes-Santos et al., 2021; Rudy et al., 2015).
Therefore, it can be speculated that glial cells participate in the patho-
mechanisms associated with neurological complications related to
ZIKV infection in the adult and aging brain, since ZIKV can signifi-
cantly change this triad.
Although glutamate plays a vital role in learning and memory,
alterations in glutamatergic signaling can lead to excitotoxicity (Rudy
et al., 2015). ZIKV may interfere with glutamate synapse mechanisms,
since it replicates in adult mice brain tissue and affects synapses and
memory; therefore, cognitive deficits could be considered as a poten-
tial comorbidity in ZIKV-infected adults (Figueiredo et al., 2019). In
addition, ZIKV infection early in life, in mice, has been associated with
long-term neuropathological and behavioral consequences, which is
accompanied by a persistent ZIKV replication (de Nem et al., 2018;
Ireland et al., 2020). One of the possible factors associated with neu-
ropathy is the levels of glutamate in astrocytes, which may result in
glutamatergic excitotoxicity through decreased glutamate transporter
activity via ROS and inflammatory cytokines (Sirohi & Kuhn, 2017).
Downregulation of excitatory amino acid transporter 2 (EAAT2) and
glutamine synthetase in astrocytes has been observed in a neuroinva-
sive respiratory virus model (Brison et al., 2014); however, at least
acutely, ZIKV exposure did not change the expression of astroglial
glutamate transporters in hippocampal slices (Bobermin et al., 2020).
Further experimental investigations of how ZIKV can imbalance gluta-
mate levels are needed, although a direct excitotoxic mechanism of
ZIKV infection, mediated by the N-methyl-D-aspartate (NMDA)
receptor, has been demonstrated in neuronal cultures (Costa
et al., 2017; Gaburro et al., 2018). Moreover, ZIKV-infected neurons
release increased levels of glutamate (Olmo et al., 2017). Interestingly,
NMDA blockers inhibited ZIKV replication and prevented neuronal
death in in vitro and in vivo experimental models (Costa et al., 2017).
These findings suggest an important pathway underlying ZIKV
induced neurological effects, since activation of NMDA receptors is a
determinant event for the excitotoxic process in neurodegenerative
diseases.
Astrocytes can also regulate extracellular glutamate levels
through hemichannels, volume-regulated anion channels, and P2X7
receptors (Duan et al., 2003; Ficker et al., 2014; Yang et al., 2019; Ye
et al., 2003). In astrocytes, P2X7 plays a crucial role in neuroinflamma-
tion and is possibly involved in the pathophysiology of ZIKV infection
(Alves et al., 2020). Furthermore, astroglial permeabilization via hemi-
channel formation and consequent glutamate release can be stimu-
lated by the pro-inflammatory cytokines, TNF-α and IL-1β (Orellana
et al., 2011), an event that may be relevant during ZIKV infection and
underlying brain damage. In line with this, the brains of convalescent
mice (1-year post infection) present cellular infiltration, surrounded by
activated astrocytes and microglia (Ireland et al., 2020), and the result-
ing neuroinflammation might increase the risk of neurodegenerative
disorders. In fact, adult mice that were neonatally infected by ZIKV
showed increased susceptibility to chemically induced seizures, neuro-
degeneration, and brain calcifications, which may be related to early
TNF-α-mediated neuroinflammation (Nem de Oliveira Souza
 10981136, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/glia.24353 by UNSA - Univ Nacional de Salta, Wiley Online Library on [06/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1798 QUINCOZES-SANTOS ET AL.

et al., 2018). The role of neuroinflammation in neurocognitive impair- been observed. The phosphorylation of cAMP responsive element
ment has also been described in adult rhesus macaques infected with binding protein (CREB), an important transcription factor that medi-
ZIKV (Hsu et al., 2022). ates learning and memory processes, decreased (Figueiredo
With regard to its molecular mechanisms in the mature brain, et al., 2019). Our group recently demonstrated, in hippocampal slices,
ZIKV has been shown to affect pathways involved in synaptic plastic- which exhibit a partially preserved neuronal circuitry and active net of
ity and inflammatory response. A reduced synaptic density in the CA3 glial cells, that acute ZIKV exposure caused a marked inflammatory
and dentate gyrus of the hippocampus, accompanied by memory response. In addition, ZIKV increased the expression of TLR2 and
impairment and compromised long-term potentiation (LTP), has also adenosine receptor A2a, both of which can modulate

F I G U R E 3 Gene interaction network and functional category of top-ranked selected diseases associated with Neurological Disorders
(MalaCards DB) in the Zika infection of glial cells. (a) Astrocytes; (b) Microglia; (c) Oligodendrocytes. The networks were built using
Cytoscape v.3.8.0.

QUINCOZES-SANTOS ET AL.
neuroinflammation and are involved in adult hippocampal neurogen-
esis and synaptic plasticity. Although the expression of synaptophysin,
widely used as a marker of synaptic plasticity, was not affected by
short-duration ZIKV exposure, extracellular levels of brain-derived
neurotrophic factor (BDNF) and S100B were decreased, suggesting
that ZIKV also affects trophic signaling. Moreover, ZIKV increased
p21 senescence-associated gene expression (Bobermin et al., 2020).
Therefore, these molecular alterations may represent a possible link
between ZIKV, neuroinflammation, and long-term neurological dis-
eases and, consequently, neurodegeneration.
In addition, altered expressions of proteins previously described
in several brain pathologies, such as AD, ASD, ALS, and PD, among
others, have been associated with ZIKV infection (Beys-da-Silva
et al., 2019, 2020). In fact, viral infections are one of the risk factors
for AD, and other clinically relevant neurotropic viruses (arboviruses,
human immunodeficiency virus, herpesviruses, and hepatitis C virus)
have previously been associated with AD (Dehhaghi et al., 2018).
With specific regard to ZIKV, infection by this virus may increase the
expression of β-amyloid and phosphorylated-Tau protein, accompa-
nied by endoplasmic reticulum (ER) stress and unfolded protein
response (UPR) in brain organoids (Lee et al., 2022). Therefore, ZIKV
infection may accelerate/aggravate clinical outcomes of neurodegen-
erative diseases and/or age-related diseases.
To corroborate the experimental data discussed in this review, we
performed a gene interaction network of neurological disorders asso-
ciated with ZIKV infection and glial cells (Figure 3). This analysis
reveals that ZIKV alters the expressions of genes associated with
immune/inflammatory responses, mainly in astrocytes and microglia,
including TNF, IL1B, IL6, TNFRSF1A, IL1R1, IFNG, TLR3, RELA, PTGS2,
NOS2, among others. Although the expressions of these inflammatory
genes can elicit an antiviral response, several of these molecules rep-
resent senescence markers, and chronic neuroinflammation is a com-
mon feature of neuropsychiatric and neurodegenerative diseases,
such as AD, ASD, ALS, PD, epilepsy, multiple sclerosis, and schizo-
phrenia. Accordingly, in vitro mechanistic studies have identified TNF-
α signaling via TNFR1 as a crucial regulatory mechanism controlling
ZIKV-induced changes in neurologic gene expression (Kung
et al., 2022). Several genes associated with cell functionality have
been identified, particularly in astrocytes, including GFAP, BDNF,
SOD2, SLC1A3, MAOA, ACHE, APOE, LDLR, which encode astrocyte
markers and proteins associated with trophic signaling, antioxidant
defenses, neurotransmitter homeostasis and cholesterol metabolism.
In oligodendrocytes, a lower number of genes were found, and these
are associated with inflammatory processes, trophic signaling, and
metabolic processes (TNFRSF1A, NTF3, MAPK8, STAT1, FABP3).
As such, the footprints left by ZIKV in glial cells may help to molec-
ularly explain the link between ZIKV and neuropsychiatric/
neurodegenerative diseases. As astrocytes presented the highest num-
ber of genes associated with neurological disorders altered by ZIKV,
these cells may represent potential key targets and cellular mediators of
the effects of ZIKV in the CNS. These molecular analyses may also pro-
vide new insights for protective strategies focused on glial cells (gliopro-
tective strategies) for preventing ZIKV-associated brain disorders.
10981136, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/glia.24353 by UNSA - Univ Nacional de Salta, Wiley Online Library on [06/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1799
5 | C O N C LU D I N G R E M A R K S
Considering the important functions of glial cells in the maintenance
of nervous system homeostasis, as well as their roles in the pathogen-
esis of neurodegenerative diseases, this review addressed functional,
cellular, and molecular mechanisms of these cells associated with
ZIKV infection, focusing on neurological complications in the adult
and aging brain. In addition, we highlight the potential association
between ZIKV infection of glial cells and the development and/or pro-
gression of neuropsychiatric/neurodegenerative disorders, which rep-
resent potential long-term consequences of viral infection, particularly
in adult and elderly populations. It is noteworthy that epidemiological
and clinical data on long-term ZIKV are still scarce and monitoring is
required, as the ZIKV epidemic is relatively recent and more concen-
trated in developing countries. Finally, by understanding the glial
effects of ZIKV, preventive/therapeutic strategies focusing on glial
cells may emerge to delay and/or prevent the development of ZIKV-
induced neurological disorders and their future consequences.
AUTHOR CONTRIBU TIONS
André Quincozes-Santos conceptualized the review. All authors wrote
the original draft of the manuscript, revised, edited, and approved the
manuscript.
ACKNOWLEDG MENTS
The authors are supported by the Brazilian funding agencies Conselho

gico (CNPq); Coor-
Nacional de Desenvolvimento Científico e Tecnolo
denação de Aperfeiçoamento Pessoal de Nível Superior (CAPES); Min-
istry of Science, Technology, Innovation and Communications
(MCTIC), Ministry of Education (MEC), Ministry of Health
(MS) through the Edital MCTIC/FNDCT-CNPq/MEC-CAPES/MS-
Decit/No 14/2016, project 440763/2016-9; Fundação de Amparo à
Pesquisa do Estado do Rio Grande do Sul (FAPERGS).
CONFLIC T OF INTER E ST STATEMENT
The authors declare no conflicts of interest.
DATA AVAILABILITY STAT EMEN T
Data sharing is not applicable to this article as no new data were cre-
ated or analyzed in this study.
OR CID
André Quincozes-Santos https://orcid.org/0000-0001-8611-4890
Larissa Daniele Bobermin https://orcid.org/0000-0001-8318-4818
Juliana M. Coelho-Aguiar https://orcid.org/0000-0001-7451-7289
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